RSC Mechanochemistry最新文献

We provide a systematic investigation of the role of atmospheric oxygen and choice of milling assembly (i.e., the milling jar and ball materials) on a prototypical medicinal mechanochemistry reaction: the copper-catalysed coupling of isocyanate and sulfonamide to form the sulfonylurea tolbutamide. Using in-house developed equipment for work under controlled-atmosphere milling conditions, we reveal that the reaction is in fact catalysed by Cu(II) species, with the conventionally used CuCl acting as a pre-catalyst, which becomes activated via aerobic oxidation during milling. Unexpectedly, the choice of milling jar material was found to have a profound effect on the coupling, with aluminium jars effectively “shutting down” reactivity, most likely by preventing CuCl oxidation. Hence, opposite to direct mechanocatalysis, a term used to describe reactions promoted by the milling jar or ball material, this observation reveals the possibility of direct mechanoinhibition – i.e., the inhibition of a mechanochemical reaction by the jar. These results highlight the importance of systematic investigations of both the milling assembly, as well as atmosphere, in understanding and controlling organic mechanochemical transformations.

Mechanochemical synthesis of Zn-laden calcium hydroxyapatite (HAP) nanocrystals was performed from a chemically precipitated monetite/brushite precursor. ZnCO₃ served as the Zn²⁺ source. Powder XRD results showed that up to 15% ZnCO₃ can be incorporated into the HAP lattice during the mechanochemical transformation of the precursors. The resulting spectral properties, as investigated using Raman and infrared spectroscopy, showed stark differences between the mechanochemically prepared sample and the control HAP and ZnCO₃ mixed sample. In particular, a peak at 874 cm⁻¹ was observed in infrared and assigned to the HAP-incorporated carbonate ion C–O (ν₂) vibration as opposed to ZnCO₃ at 834 cm⁻¹ indicating that not only Zn²⁺ but also CO₃²⁻ is incorporated into the HAP lattice. Distinct thermal properties were also observed in the thermal analysis of mechanochemically reacted Zn-HAP with the endothermic peak at 235 °C completely absent as opposed to the mixed control of HAP and ZnCO₃. Electron microscopy analysis showed ∼10 × 40 nm HAP nanocrystals formed with a uniform Zn²⁺ ion distribution within them, especially at low 5% ZnCO₃ loading. Zn²⁺ dissolution experiments in soil-relevant 2% citric acid solution showed a distinct delayed dissolution pattern of mechanochemically obtained Zn-HAP with six-fold slower dissolution than that of mixed HAP and ZnCO₃, a commonly used zinc supplement. This study presents room-temperature synthesis methods of plant nutrient-laden HAP with tunable dissolution kinetics needed for efficient nutrient uptake.

Organobismuth compounds have been known for centuries as substances of medical interest, and continue to be used in medicine today. Bismuth active pharmaceutical ingredients (APIs) are used as digestive aids, including in combating Helicobacter pylori, showing antiviral properties. Here we report the mechanochemical synthesis of bismuth gallate and bismuth citrate. In addition, we revisit the previously reported mechanochemical synthesis of bismuth(III) di- and trisalicylate. In the case of bismuth citrate, which has an unknown structure, we show that hydration induces a reversible transformation to a large (possibly cubic) unit cell.

Deoxygenation of phosphine oxides is an important method for the synthesis of valuable organophosphine compounds and recycling of phosphorus resources. However, existing solution-based deoxygenation protocols usually require long reaction times, significant amounts of potentially harmful organic solvents, and inert gas atmospheres. In addition, reactions of poorly soluble phosphine oxides are challenging and often inefficient. Herein, we demonstrate that a high-temperature mechanochemical protocol enables the highly efficient solvent-free deoxygenation of phosphine oxides with hydrosilanes in the presence of a phosphoric acid additive. These reactions were rapid and completed within 30 min for most substrates. Notably, this is the first practical deoxygenation of phosphine oxides in which all synthetic operations can be carried out in air. A preliminary study on the mechanochemical catalytic Wittig reaction is also described.

The Biginelli reaction, a crucial multicomponent reaction, was investigated involving 2-hydroxy-1,4-naphthoquinone (lawsone), p-substituted benzaldehydes, and ureas. Surprisingly, the classic Biginelli cyclized DHPM was not observed under various experimental conditions. Mechanochemical conditions, unlike traditional liquid phase conditions, led to the unprecedented formation of a series of ‘Biginelli-linear’ lawsone derivatives with high yields. The observed outcomes were consistent with DFT theoretical predictions, highlighting the preference for the Michael adduct under liquid conditions and the energetically implausible cyclization pathway for the classic DHPM compound. Additionally, the study achieved the novel cyclization of a ‘Biginelli-linear’ lawsone derivative into a cyclic carbamate for the first time.

We demonstrate the first use of Resonant Acoustic Mixing (RAM) without bulk solvent for the synthesis of short oligonucleotide fragments. Using the modified H-phosphonate approach, DNA, RNA, and 2′-modified nucleotides were successfully coupled to 3′-protected nucleosides in high yields (63–92%) while reducing solvent volume by 90%. In addition to synthesizing protected phosphodiester (PO) dimers and trimers, we also synthesized protected phosphorothioate (PS) dimers in good yields (63–65%). Using phosphoramidite chemistry, we were similarly able to reduce the solvent volume by 90% while coupling DNA phosphoramidites (58–92%) and RNA phosphoramidites (55–95%) with 3′-protected nucleosides in high yields followed by traditional oxidation with iodine in solution. Both strategies were successfully scaled up to multi-gram quantities which was facilitated by the use of RAM, offering the potential for larger scale-up, up to hundreds of kilograms continuously.

The heavy Group 15 allyls (E = As, Sb, Bi; [A′] = [1,3-(SiMe₃)₂C₃H₃]⁻) can be prepared either in solution or mechanochemically, and exist in two diastereomeric forms of C₁ and C₃ symmetry. For E = As and Sb, their ratio varies with the method of preparation: the C₁ diastereomer is the major form by both methods, but the mechanochemical route increases the C₁ : C₃ ratio compared to synthesis in hexanes solution. The difference in selectivity has previously been identified as a consequence of the layered crystal lattices of the EX₃ reagents, which provide a templating effect through an anisotropic grinding environment. How this selectivity changes with other typical mechanochemical variables is explored here, including the use of different reagents and LAG solvents, pre-grinding the reagents, the use of different milling media (stainless steel, Teflon, etc.) and apparatus (mixer mill, planetary mill), and the number and size of balls. The extent to which the anisotropic environment is either maintained or modified during synthesis (especially by LAG and the choice of metal reagent) affects the diastereomeric ratio.

Despite considerable advancements in mechanochemical amide couplings, there is a paucity of studies addressing chemoselective issues in these transformations, such as the tolerance of unmasked hydroxyl groups. In view of the high practical significance of amide coupling reactions in the synthesis of active pharmaceutical ingredients (APIs), we aimed to investigate the tolerance of unprotected hydroxyls in carboxylic acids towards various reported mechanochemical amide coupling conditions. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) in combination with ethyl acetate as a liquid-assisted grinding (LAG) additive was revealed as the most selective amide coupling system that delivers 76–94% yields of amides from a range of hydroxycarboxylic acids, including N-Boc-protected amino acids serine and tyrosine. The EDC-mediated amide coupling protocol was employed in the synthesis of imatinib, an anticancer drug included in the World Health Organization's List of Essential Medicines. The target API was synthesized in an overall 86% yield and 99% HPLC purity through a two-step mechanochemical C–N bond assembling reaction sequence starting from 4-(hydroxymethyl)benzoic acid.

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Tribochemical decomposition of thin-film synthetic iron disulfide and mineral iron pyrite was studied using a combination of operando mass-spectrometry coupled to ultrahigh vacuum tribochemical cell and the gas expansion system. The composition and kinetics of gas emission were analyzed using an original methodology. It was found that carbon-containing gases were dominating. The sulfur-containing gases comprised H₂S, COS and CS₂. The latter two were unexpected. The emission of these gases was traced back to solid-state chemical reactions kinetically controlled by the precursor concentrations and driven through non-thermal mechanisms, which we tentatively assigned to formation of sulfur radicals.